Disposition and metabolism of a novel antineoplastic agent, 4-tert-butyl-[3-(2-chloroethyl)ureido]benzene, in mice.
1-Aryl-3-(2-chloroethyl)ureas are new agents that have shown promising cytotoxic and antineoplastic activities. In this work, we studied the disposition and metabolism of one of these molecules, 4-tert-butyl-[3-(2-chloroethyl)ureido]benzene (tBCEU). tBCEU was labeled with 14C and 13C in the urea function and in the chloroethyl moiety. After ip administration of the molecule labeled in the urea function, radioactivity was widely distributed in the whole organism, including the brain. HPLC analysis of plasma showed that tBCEU was extensively metabolized, with <20% being found in the plasma as unchanged tBCEU 1 hr after administration. One main metabolite was identified by NMR and MS analysis as N-[4-(2-hydroxy-1, 1-dimethylethyl)phenyl]urea, widely conjugated to glucuronic acid. The same metabolite was found in the urine. After administration of tBCEU labeled in the chloroethyl moiety, the same tissue affinities were observed, but the decrease of total radioactivity in blood and tissues was slower than that observed for the molecule labeled in the urea function. HPLC analysis of urine showed the presence of two main metabolites, identified by MS as thiodiacetic acid and its sulfoxide. From these results, we can deduce that the metabolic pathway of tBCEU involves N-dealkylation of the urea portion of the molecule and hydroxylation of the tert-butyl group. The strong cytochrome P450 reactivity of the carbon adjacent to the urea portion of tBCEU is probably related to particular sensitivity to oxidation at this position, based on the chemical structure of tBCEU. These results can explain the fact that the cytotoxic effect of tBCEU is not due to DNA alkylation, in contrast to that of its parent molecule, chloroethylnitrosourea.
Maurizis
J C
JC
INSERM U 71, Pavillon Saint-François d'Assise, Centre Hospitalier Universitaìre de Québec.
Rapp
M
M
Azim
E M
EM
Gaudreault
R C
RC
Veyre
A
A
Madelmont
J C
JC
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002247:Carbon Isotopes; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D008658:Inactivation, Metabolic / Q000502:physiology*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D014508:Urea / Q000031:analogs & derivatives / Q000032:analysis / Q000737:chemistry; D014556:Urine / Q000737:chemistry
D000970:Antineoplastic Agents; D002247:Carbon Isotopes; D010671:Phenylurea Compounds; C084239:4-tert-butyl-(3-(2-chloroethyl)ureido)benzene; D014508:Urea